Therapeutic Targeting of Anaplastic Lymphoma Kinase in Lung Cancer: A Paradigm for Precision Cancer Medicine

摘要

Abstract The anaplastic lymphoma kinase (ALK) receptor tyrosine kinase was initially discovered as a component of the fusion protein nucleophosmin (NPM)-ALK in anaplastic large-cell lymphoma (ALCL). Genomic alterations in ALK, including rearrangements, point mutations, and genomic amplification, have now been identified in several malignancies, including lymphoma, non-small cell lung cancer (NSCLC), neuroblastoma, inflammatory myofibroblastic tumor, and others. Importantly, ALK serves as a validated therapeutic target in these diseases. Several ALK tyrosine kinase inhibitors (TKI), including crizotinib, ceritinib, and alectinib, have been developed, and some of them have already been approved for clinical use. These ALK inhibitors have all shown remarkable clinical outcomes in ALK-rearranged NSCLC. Unfortunately, as is the case for other kinase inhibitors in clinical use, sensitive tumors inevitably relapse due to acquired resistance. This review focuses on the discovery, function, and therapeutic targeting of ALK, with a particular focus on ALK-rearranged NSCLC. Anaplastic lymphoma kinase (ALK) was initially discovered as the fusion gene nucleophosmin (NPM)-ALKin anaplastic large-cell non-Hodgkin lymphoma (ALCL; ref. 1). More than a decade later, the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion gene was first detected in lung cancer (2), andnumerous other ALK fusions, differing by the N-terminal gene fusion partner, have since been identified in lung and other cancers. In addition, ALK point mutations have been detected in neuroblastoma and thyroid cancers (3-6).